PROSTATE CANCER STUDIES

Surgery vs. Radiation vs. Nothing

PIVOT (9,28) - RP vs. Observation
  • non-significant difference in overall survival with a median follow-up of 10-years in those undergoing observation or radical prostatectomy (RP)
  • 47.0 vs. 49.9%
  • Early PSA screening era
  • Results contrast SPCG-4

Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) (23,27) - RP vs. Observation
  • RP superior in men <65yrs compared to AS
  • Significant improvement in RP prostate cancer specific mortality (14.6 vs. 20.7%), as well as all-cause mortality (46.1 vs. 52.7%) at 15 years in men under 65 years old.
  • RR of 0.68 with RP 
  • Pre-PSA screening era. 
​
PROTECT (13,14) - RP vs. RT vs monitoring
  • RP vs. RT vs monitoring showed no difference in PC mortality at 10 years.
  • The monitoring group had double the rate of distant mets.
  • QOL= RP erections and incontinence worse; RT had worse bowel function
  • 50% of monitored patients were ultimately treated w/ RP or RT. 
  • At a median of 10 years, there was no difference in prostate cancer-specific mortality among the groups. The active monitoring group had a higher rate of metastasis, but had less impact on urinary, sexual, and bowel function. 

However, when you pool PROTECT, PIVOT and SPCG-4 data, there is a consistent risk reduction in prostate cancer (0.65) and overall mortality (0.90) from RP. (29)

Veterans Administration Cooperative Urological Research Group (VACURG) (30)  - RP vs. placebo
  • Smaller than the above studies
  • Initially showed benefit from RP in stage I PCa, however after adjusted for imbalance in age distribution this difference became statistically insignificant


Nonmetastatic Castrate Resistant Prostate Cancer (CRPC)

ENZALUTAMIDE - PROSPER - 1401 men Enzalutamide in castrate resistant nonmetastatic prostate cancer (ie. no image proven metastasis) (11,33)
  • Enzalutamide prolonged metastasis free survival (MFS) from 14.7 to 36.6 months at average follow-up of 18mo (11)
  • Time to progression lengthened from 3.9mo to 37.2mo at follow up of 18mo (11)
  • At 48mo average follow up there was an increase in OS of 67mo vs 56mo with enzalutamide. 

APALUTAMIDE - SPARTAN - Apalutamide vs. placebo in castrate resistant nonmetastatic prostate cancer (8)
  • Increased MFS 40.5mo vs. 16.6mo
  • PSA progression 3.7mo in placebo, not yet reached in apalutamide​​
  • Side effects w/ apalutamide vs. placebo: rash (23.8% vs. 5.5%), hypothyroidism (8.1% vs. 2.0%), and fracture (11.7% vs. 6.5%).​

DAROLUTAMIDE - ARAMIS - Darolutamide in castrate resistant nonmetastatic prostate cancer
  • increased MFS 40.4 mo vs. 18.4 (24)
  • increased OS by 6% at 3years. (32)

NOTES:
  • PROSPER, SPARTAN AND ARAMIS all had patients with PSADT <10mo with more then 2/3 had PSADT <6mo and >90% not on a bone targeted agent
  • Apalutamide & enzalutamide had higher fatigue (27-30%) and  falls (12-14%) than darolutamide (12% fatigue, 4.2% falls) and apalutamide had fractures in 12% vs. darolutamide (4.2%)
  • Apalutamide was only one to have a rash

Neoadjuvant Chemotherapy

One study found no benefit for intermediate and high risk patients. (26)

Metastatic Hormone Sensitive Prostate Cancer mHSPC

 RTOG = gleason >7, mHSPC: ADT+radiation vs. ADT+radiation+docetaxel
  • 6 year survival 65% w/ docetaxel vs. 55% without

GETUG-AFU 15  (385 patients)
  • After a median follow up of 82.5 months, the median OS was 60.9 months in the docetaxel plus ADT arm and 46.5 months in the ADT arm 

CHAARTED and STAMPEDE both show docetaxel improved survival in men with high-risk metastatic hormone-sensitive prostate cancer,

Abiraterone LATTITUDE (34), Enzalutamide ARCHES (35) ENZAMET (37) and Apalutamide TITAN (36) ​all had trials with more than 1000 patients.  LATITUDE was prior to docetaxal whereas 20% in ARCHES and TITAN got it and 45% of ENZAMET got docetaxel.  LATITUDE was 98% high volume disease vs. 52-62% of ARCHES, ENZAMET and TITAN had high volume disease.  All 4 showed improvement in PFS and LATITUDE showed improved OS.  An important finding was that adding docetaxel to these drugs did not improve survival and actually had lower OS if added.  The ARASENS trial is looking at daralutamide  in this application.   

DOCETAXEL is given over 18 weeks with prednisone and adverse events are fatigue and neuropathy. 

Metastatic Castrate Resistant Prostate Cancer (mCRPC)

 PLATO - Enzalutamide + abiraterone no different than abiraterone alone in mCRPC (18)

 LATITUDE - comparing abiraterone  vs. docetaxel (both with ADT)
  • abiraterone (+prednisone) + ADT provides similar results to docetaxel + ADT in mCSPC T
  • abiraterone + prednisone has better QOL and less pain than ADT alone (1,16)

STAMPEDE (2962 patients) comparing multiple modalities
  • Has 9 arms
  • abiraterone (+prednisone) + ADT superior to ADT in mHSPC, 22mo OS ? (vs. 15?)
  • Also looking at ADT vs. ADT + RT (600 patients)
  • enzalutamide + abiraterone + prednisone + ADT (15)

CHAARTED (790 patients)  docetaxel + ADT is superior to ADT in newly diagnosed mCRPC, 13.6mo increased OS
  • w/ high volume disease (visceral mets, >4 bone mets w/ 1 outside vertebral bodies & pelvis) docetaxel + ADT = 17mo increased OS
  • QOL better for first 3 mo w/ ADT, then better at 6 and 12 mo w/ docetaxel + ADT
  • All patients eventually required 2nd line therapy
**update to CHAARTED (22)
  • 16.8mo extension in  OS for high volume disease, those with low volume disease (<4 mets) did not benefit

TAX327 (2004) = docetaxel superior to mitoxantrone in mCRPC, 3 month increase OS
  • First study showing docetaxel superior

TROPIC (2010) = cabazitaxel superior to mitoxantrone if progression after docetaxel in mCRPC, 3 month increased 2.4 mo OS

FIRSTANA first line mPC treatment: docetaxel vs. cabazitaxel (5)
  • 159 centers w/ 1,168 patients
  • Docetaxel, cabazitaxel 20mg, cabazitaxel 25mg have very similar OS (24.3, 24.5, 25.2 mo) and PRS (5.3, 4.4, 5.1 mo)
  • 25% docetaxel got grade 1-2 neuropathy, 2% death from adverse events
  • 0.8% death rate from 20mg cabazitaxel, 2.8% death rate from 25mg cabazitaxel
  • Radiographic tumor responses were numerically higher for C25 (41.6%) versus D75 (30.9%)
  • Rates of grade 3 or 4 treatment-emergent adverse events were 41.2%, 60.1%, and 46.0% for C20, C25, and D75, respectively
​
COU-302 mCRPC post docetaxel
  • abiraterone + prednisone then chemo if progression vs. placebo + prednisone = 4.2mo increased OS
  • if no pain, normal ALP/LDH, <10 bone mets, MS 42.6mo

PROCEED (Sipuleucel-T)
  • AA men had 11mo survival benefit compared to caucasians
  • 4.1mo overall increase in OS for all patients

SEARCH

SU2C/PCF/AACR - 124 patients resistant to abiraterone / enzalutamide3
  • PC resistant to abiraterone or enzalutamide 13% had small cell, 26% has intermediate atypical carcinomas, 26% mixed histologies
  • non-adenocarcinoma PC have much worse progrnosis

Halabi et al. 2016 -  >8000 patients w/ mCRPC
  • if only LN = 31.6mo OS
  • lung mets = 19.3mo OS
  • bone mets = 21.3mo OS
  • liver mets = 13.5mo OS​


RCT of 72 patients compared low dose abiraterone to normal dosage. (20)

de Wit et al 2020 - 255 patients post docetaxel and abiraterone/enzalutamide randomized to cabazitaxel vs. abiraterone or enzalutamide found cabazitaxel had a longer image based progresison free survival (8.0mo vs. 3.7mo) and OS (13.6mo vs. 11.0mo) (31)

​

BONE HEALTH

ALSYMPCA

RADIATION STUDIES

Some studies show 45% of PSM will not recur w/ f/u time of >10yrs and recent data show w/ 20 yr f/u no difference seen in distant mets & OS if adjuvant RT after PSM.  Gleason score at site of margin is very important.
​RTOG 9601
  • The addition of 24 months of antiandrogen therapy, in the form of bicalutamide (Casodex) daily, to salvage radiation therapy in men with biochemical recurrence following radical prostatectomy improved long-term survival and lowered the incidence of metastatic disease and death from prostate cancer. (17)
SWOG 87-94
  • 35% post prostatectomy had persistent PSA
  • The only trial to show OS w/ adjuvant radiotherapy
EORTC 22911
  • 35% post prostatectomy had persistent PSA
ARO 96-02 (German)
  • Only trial to require undetectable PSA prior to enrollment
CHHiP; PROFIT; HYPRO
  • Suggest that 19 or 20 days vs. 37 or 39 days of RT have similar cancer control but possibly mildly increased GI toxicity (except HYPRO)
  • Awaiting long term follow up
ASCENDE-RT (Andorgen Supression Combined with Elective Nodal and Dose Escalated Radiation Therapy)
  • Brachytherapy boost improves PSA response but has increased genitourinary toxicity (18%)
FOSSATI et al (2017) Long-term Impact of Adjuvant Versus Early Salvage Radiation Therapy in pT3N0 Prostate Cancer Patients Treated with Radical Prostatectomy
  • Each increase in PSA greater than 0.2 decreases the cure rate by 2.6% each 0.1 ng/ml rise
FOSSATI et al (2016) Assessing the Optimal Timing for Early Salvage Radiation Therapy in Patients with Prostate-specific Antigen Rise After Radical Prostatectomy.
  • If multiple risk factors, cure rate may decrease by 10% for each 0.1 ng/ml PSA increase
CARRIE et al (2016) Salvage radiotherapy with or without short-term hormone therapy for rising prostate-specific antigen concentration after radical prostatectomy
  • level 1 evidence 6 month ADT plus salvage RT in reducing PSA recurrence
HORRAD - nederlands - mPca hormone vs. hormone + RT

LYMPHADENECTOMY

Retrospective multi-institution study of 728 patients who underwent salvage RT for BCR post RP had increased survival with increased number of nodes removed at time of RP. (12)

IMAGING

PROMIS - MRI increases detection of clinically significant PC (10)

PRECISION - MRI with or without targeted biopsy is non-inferior to standard systemic biopsy and more accurate detecting clinically significant disease with fewer cores (21)
See Imaging for more info

GENOMICS

STOCKHOLM 3  - germline DNA testing + PSA has better detection than PSA screened alone

RISK FACTORS

Prostate Cancer Prevention Trial - Finasteride reduces number of overall cancers, may increase high grade
  • Very large study= more than 4000 patients
  • Total prostate cancer in 18% finasteride vs 24% placebo
  • High grade cancer (Gleason 7, 8, 9, 10)  in 6.4% finasteride vs. 5.1% placebo​ (2)-

Wallerstedt et al - Finasteride reduces overall number of PCa, did not statistically significantly affect long term risk of Gleason 8-10
  • Swedish study of 23,000 patients exposed to 5-ARI
  • Treatment with 5-ARI decreased the risk for overall PC, and the effect was larger with longer time of exposure (0.1 to 2 years: hazard ratio [HR] = 0.81, 95% confidence interval [CI] = 0.71 to 0.93; 2 to 4 years: HR = 0.39, 95% CI = 0.32 to 0.47; 4 to 6 years: HR = 0.40, 95% CI = 0.31 to 0.52; and 6 to 8 years: HR = 0.31, 95% CI = 0.16 to 0.60).
  • 5-ARI decreased the risk for PC with Gleason Scores 6 and 7
  • Did not statistically significantly affect the long-term risk of being diagnosed with a PC with a Gleason Score of 8 to 10 with up to eight years of treatment.  (3)

MP14-17  - AA men have 31% increased risk of biochemical recurrence post-RP when adjusted comparisons performed (4)

OTHER

VAIL
AFFIRM
​TERRAIN

TESTOSTERONE REPLACEMENT
Testosterone replacement didn't increase risk of prostate cancer in this large study, most patients on TRT had low risk disease. (6)
DRE demonstrated prognostic usefulness when prostate specific antigen was greater than 3 ng/ml, limited usefulness for less than 2 ng/ml and marginal usefulness for 2 to 3 ng/ml. These findings support the restriction of digital rectal examination to men with higher prostate specific antigen as a reflex test to improve specificity. It should not be used as a primary screening modality to improve sensitivity. (7)

​One large systemic review of 20 studies found that men in the lowest tenth of free testosterone concentration had a lower risk of overall prostate cancer(18)

One interesting article reviewed the implications of low grade prostate cancer and renal transplantation. (25)

  1. Chi, Kim N., et al. "Patient-reported outcomes following abiraterone acetate plus prednisone added to androgen deprivation therapy in patients with newly diagnosed metastatic castration-naive prostate cancer (LATITUDE): an international, randomised phase 3 trial." The Lancet Oncology(2018).
  2. Thompson, Ian M., et al. "The influence of finasteride on the development of prostate cancer." New England Journal of Medicine 349.3 (2003): 215-224.
  3. Wallerstedt, Anna, et al. "Risk of Prostate Cancer in Men Treated With 5α-Reductase Inhibitors—A Large Population-Based Prospective Study." JNCI: Journal of the National Cancer Institute (2018).
  4. Nyame, Yaw, et al. "MP14-17 INCREASED RISK OF BIOCHEMICAL FAILURE AFTER RADICAL PROSTATECTOMY AMONG AFRICAN AMERICAN MEN WITH HIGH RISK PROSTATE CANCER." The Journal of Urology 197.4 (2017): e168.
  5. Oudard, Stéphane, et al. "Cabazitaxel versus docetaxel as first-line therapy for patients with metastatic castration-resistant prostate cancer: A randomized phase III trial—FIRSTANA." Journal of Clinical Oncology 35.28 (2017): 3189-3197.
  6. Loeb, Stacy, et al. "Testosterone replacement therapy and risk of favorable and aggressive prostate cancer." Journal of Clinical Oncology 35.13 (2017): 1430.
  7. Halpern, J. A., C. Oromendia, and J. E. Shoag. "Use of Digital Rectal Examination as an Adjunct to Prostate Specific Antigen in the Detection of Clinically Significant Prostate Cancer." J Urol (2017).
  8. Smith, Matthew R., et al. "Apalutamide treatment and metastasis-free survival in prostate cancer." New England Journal of Medicine 378.15 (2018): 1408-1418.
  9. Wilt, Timothy J., et al. "Radical prostatectomy versus observation for localized prostate cancer." New England Journal of Medicine 367.3 (2012): 203-213.
  10. Ahmed, Hashim U., et al. "Diagnostic accuracy of multi-parametric MRI and TRUS biopsy in prostate cancer (PROMIS): a paired validating confirmatory study." The Lancet389.10071 (2017): 815-822.www.ncbi.nlm.nih.gov/pubmed/28110982
  11. Hussain, Maha, et al. "Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer." New England Journal of Medicine 378.26 (2018): 2465-2474.
  12. Fossati, Nicola, et al. "More Extensive Lymph Node Dissection at Radical Prostatectomy is Associated with Improved Outcomes with Salvage Radiotherapy for Rising Prostate-specific Antigen After Surgery: A Long-term, Multi-institutional Analysis." European urology (2018).
  13. Hamdy, Freddie C., et al. "10-year outcomes after monitoring, surgery, or radiotherapy for localized prostate cancer." New England Journal of Medicine 375.15 (2016): 1415-1424.
  14. Donovan, Jenny L., et al. "Patient-reported outcomes after monitoring, surgery, or radiotherapy for prostate cancer." New England Journal of Medicine 375.15 (2016): 1425-1437.
  15. James, Nicholas D., et al. "Abiraterone for prostate cancer not previously treated with hormone therapy." New England Journal of Medicine 377.4 (2017): 338-351.
  16. Fizazi, Karim, et al. "Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer." New England Journal of Medicine 377.4 (2017): 352-360.
  17. Shipley, William U., et al. "Radiation with or without antiandrogen therapy in recurrent prostate cancer." New England Journal of Medicine 376.5 (2017): 417-428.
  18. Attard, Gerhardt, et al. "Abiraterone Alone or in Combination With Enzalutamide in Metastatic Castration-Resistant Prostate Cancer With Rising Prostate-Specific Antigen During Enzalutamide Treatment." Journal of Clinical Oncology 36.25 (2018): 2639.​
  19. Watts, Eleanor L., et al. "Low Free Testosterone and Prostate Cancer Risk: A Collaborative Analysis of 20 Prospective Studies." European urology (2018).
  20. Szmulewitz, Russell Z., et al. "Prospective international randomized phase II study of low-dose abiraterone with food versus standard dose abiraterone in castration-resistant prostate cancer." Journal of clinical oncology: official journal of the American Society of Clinical Oncology 36.14 (2018): 1389.
  21. Kasivisvanathan, Veeru, et al. "MRI-targeted or standard biopsy for prostate-cancer diagnosis." New England Journal of Medicine 378.19 (2018): 1767-1777.
  22. Kyriakopoulos CE, Chen TH, Carducci MA, et al: Chemohormonal therapy in metastatic hormone-sensitive prostate cancer: Long-term survival analysis of the randomized phase III E3805 CHAARTED trial. J Clin Oncol 36:1080–1087, 2018 
  23. Bill-Axelson, Anna, et al. "Radical prostatectomy or watchful waiting in early prostate cancer." New England Journal of Medicine 370.10 (2014): 932-942.
  24. Fizazi, K., Shore, N., Tammela, T. L., Ulys, A., Vjaters, E., Polyakov, S., … Kuss, I. (2019). Darolutamide in Nonmetastatic, Castration-Resistant Prostate Cancer. The New England Journal of Medicine, 380(13), 1235–1246.​
  25. Aminsharifi, Alireza, et al. “Evaluation and Active Treatment versus Active Surveillance of Localized Prostate Cancer in Renal Transplant Patients in the Era of Low and Very Low Risk Prostate Cancer.” The Journal of Urology, vol. 202, no. 3, 2019, pp. 469–474.
  26. Kellokumpu-Lehtinen, Pirkko-Liisa, et al. “Docetaxel Versus Surveillance After Radical Radiotherapy for Intermediate- or High-Risk Prostate Cancer—Results from the Prospective, Randomised, Open-Label Phase III SPCG-13 Trial.” European Urology, 2019.
  27. Bill-Axelson, Anna, et al. “Radical Prostatectomy or Watchful Waiting in Prostate Cancer — 29-Year Follow-Up.” The New England Journal of Medicine, vol. 379, no. 24, 2018, pp. 2319–2329.
  28. Wilt, Timothy J., et al. “Follow-up of Prostatectomy versus Observation for Early Prostate Cancer.” The New England Journal of Medicine, vol. 377, no. 2, 2017, pp. 132–142.
  29. Kilpeläinen, Tuomas P., et al. “Randomized Trials Show a Consistent Benefit of Radical Prostatectomy on Mortality Outcomes.” The Journal of Urology, 2019.
  30. P, Iversen, et al. “Radical Prostatectomy versus Expectant Treatment for Early Carcinoma of the Prostate: Twenty-Three Year Follow-up of a Prospective Randomized Study.” Scandinavian Journal of Urology and Nephrology, vol. 172, 1995, pp. 65–72.
  31. de Wit, Ronald, et al. "Cabazitaxel versus abiraterone or enzalutamide in metastatic prostate cancer." New England Journal of Medicine 381.26 (2019): 2506-2518.
  32. Fizazi, Karim, et al. "Nonmetastatic, Castration-Resistant Prostate Cancer and Survival with Darolutamide." New England Journal of Medicine 383.11 (2020): 1040-1049.
  33. ​Sternberg, Cora N., et al. "Enzalutamide and Survival in Nonmetastatic, Castration-Resistant Prostate Cancer." New England Journal of Medicine (2020).
  34. ​Fizazi, Karim, et al. "Abiraterone acetate plus prednisone in patients with newly diagnosed high-risk metastatic castration-sensitive prostate cancer (LATITUDE): final overall survival analysis of a randomised, double-blind, phase 3 trial." The Lancet Oncology 20.5 (2019): 686-700.
  35. ​Armstrong, Andrew J., et al. "ARCHES: a randomized, phase III study of androgen deprivation therapy with enzalutamide or placebo in men with metastatic hormone-sensitive prostate cancer." Journal of Clinical Oncology 37.32 (2019): 2974-2986.
  36. ​Chi, Kim N., et al. "Apalutamide for metastatic, castration-sensitive prostate cancer." New England Journal of Medicine 381.1 (2019): 13-24.
  37. ​Davis, Ian D., et al. "Enzalutamide with standard first-line therapy in metastatic prostate cancer." New England Journal of Medicine 381.2 (2019): 121-131.
Proudly powered by Weebly